Biological function and transcriptional regulation of mouse peptidylarginine deiminase type IV gene, Padi4

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Peptidylarginine deiminase is a enzyme which convert arginine residues to citrulline residues. We reported that genomics of murine PAD are involved into five gene cluster located in 4E1 region, resembling those of human PAD gene cluster. Recent study disclosed the association of functional haplotypes of the gene PADI4 (orthologue to Padi4) with rheumatoid arthritis. Therefore, function of PAD4 and characterization of the elements regulating PADI4 gene expression using experimental animals is crucial to understanding their involvement in tissue physiology and pathological conditions. We made monoclonal antibodies against murine PAD4 and found the nuclear localization of this enzyme in the peritoneal macrophage by immunohistochemisty of the antibody. Furthermore, pristine introduced into peritoneal cavity of mouse induced the expression of PAD4 gene and deiminated U1-70K peptide of snRNP. These data suggested that the conversion of arginine residues of U1-70K into citrulline residues evokes systemic lupus erythematosus. In fact, the PAD4 could deiminate the peptide of U1-70K, whereas the deimination of p30gag from MLV was not observed. These findings indicated that U1-70K is a specific substrate for PAD4 in the nucleus. Taken together, our research supported by this grant revealed the possible mechanism of autoantibody disease via the deimination of nuclear protein.